Abstract International efforts to characterize cancer genomes now provide us with an initial view of the mutations and copy number alterations that occur in human cancers. These efforts have expanded our knowledge of known oncogenic pathways and have identified new classes of oncogenes and tumor suppressor genes. However, it is now also clear that most epithelial cancers harbor hundreds of genetic alterations as a consequence of genomic instability, which complicates efforts to identify mutations critical for tumor maintenance and drives tumor heterogeneity. Moreover, it remains unclear which of these alterations confers on the tumor cell the ability to evade the immune system. The emerging clinical success of checkpoint blockade is tempered by the observation that most patients do not respond to immunotherapy. New immunotherapy targets are needed to improve tumor responses and guide rational combination immunotherapy to overcome resistance. Identifying genes that are essential for tumor survival and immune evasion will accelerate the development of new molecularly targeted therapeutics. Over the past several years, we have developed and deployed high throughput genetic and bioinformatics approaches to identify and credential cancer targets. Specifically, we have performed genome scale loss of function and gain of function screens in large sets of human cancer cell lines and patient-derived models and have identified new oncogenes and synthetic lethal interactions. The scale of these experiments has allowed us to overcome the inherent heterogeneity of cancers and to classify cancer dependencies and their context, which is essential for the initiation of drug discovery efforts. In this application, we propose to use these studies as a foundation for a new Dana-Farber Cancer Institute CTD2 Center. This Center will focus on the identification of and credentialing cancer targets, developing the means to rationally define combination therapies, and the identification of genes that modulate the response to immunotherapeutics, all through the use of novel in vitro and in vivo HT genetic and bioinformatic approaches. We will continue to make the outputs of these studies readily available to the scientific community and to participate in CTD2 Network activities. We anticipate that this Center will provide the cancer research community with information that will facilitate the prioritization of targets based on both genomic and functional evidence, inform the most appropriate genetic context for downstream mechanistic studies and facilitate the translation of this information into therapeutics and diagnostics.